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Signaling in neural progenitors and a revised view of lateral inhibition

Signaling in neural progenitors and a revised view of lateral inhibition

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Dynamic Notch signaling in neural progenitor cells and a revised view of lateral inhibition Ryoichiro Kageyama, Toshiyuki Ohtsuka, Hiromi Shimojo & Itaru Imayoshi In the developing mammalian nervous system, neural progenitor cells first express the Notch effector Hes1 at variable levels and then proneural genes and Notch ligands in salt-and-pepper patterns. Recent real-time imaging analysis indicates that Hes1 expression in these cells oscillates with a period of about 2–3 h. Furthermore, the proneural gene Neurogenin-2 ( Ngn2 ) and the Notch ligand gene Deltalike-1 ( Dll1 ) are expressed cyclically in neural progenitor cells under the control of Hes1 oscillation but are expressed continuously in postmitotic neurons, which lose Hes1 expression. Hes1-driven Ngn2 and Dll1 oscillations seem to be advantageous for maintenance of a group of cells in an undifferentiated state by mutual activation of Notch signaling. This dynamic mode of gene expression would require a revision of the traditional view of how Notch-mediated lateral inhibition operates in the developing mammalian nervous system. The Notch signaling pathway regulates cell differentiation by means of intercellular communication between adjacent cells 1–3 . In the develop- ing mammalian nervous system, the products of the proneural genes Mash1 and Ngn2 induce expression of Notch ligands such as Deltalike1 (Dll1), which activate Notch signaling in neighboring cells 4 ( Fig. 1 ). Upon activation, the transmembrane protein Notch is processed and releases the Notch intracellular domain (NICD), which moves from the transmembrane region to the nucleus, where it forms a complex with the DNA-binding protein RBPj. The NICD-RBPj complex then induces expression of the basic helix-loop-helix factors Hes1 and Hes5, which repress expression of proneural genes (and Notch ligand genes), thereby inhibiting neuronal differentiation and maintaining neural progenitor cells 1–3 ( Fig. 1 ). This intercellular regulation is called ‘lateral inhibition’ because it inhibits the neighboring cells from becoming the same cell type. In the absence of this pathway, all neural progenitors prematurely differentiate into early-born cell types without giving rise to a sufficient number and a full spectrum of cells. Thus, the Notch signaling pathway leads to production of a diversity of cell types from apparently equivalent cells and is essential in formation of complex brain structures. The classic view of Notch signaling In the developing mammalian nervous system, neural progenitors initially undergo proliferation only, and then subsets of cells begin neuronal differentiation, while others remain as progenitors. During these processes, proneural genes and Notch ligand genes are expressed at various levels in the ventricular zone, forming ‘salt-and-pepper’ patterns of gene expression. Notch-mediated lateral inhibition con- tributes to formation of salt-and-pepper patterns, but the precise mechanism by which this process generates cells with various expres- sion levels is not known. The current view of Notch-mediated lateral
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